PROJECT SUMMARY Tobacco use remains the foremost cause of preventable deaths in the U.S. and worldwide. Advancing new smoking cessation therapies, including those with novel pharmacological targets, is a critical public health priority. The serotonin (5-hydroxtytryptamine; 5-HT) system is broadly implicated in the regulation of reward- related behavior, including drug seeking, in part reflecting its modulatory role in dopamine (DA) function. Historically, efforts to advance 5-HT drugs as addiction treatments have been complicated by the diversity of 5- HT receptor subtypes and their divergent influences on behavior, as well as unwanted side effects characteristic of non-selective 5-HT agents. However, the subsequent development of highly selective 5-HT receptor ligands has allowed for targeted investigations of 5-HT receptor subtypes in preclinical models of addiction. These studies show that targeted manipulation of the serotonin 5-HT2C receptor alters drug-related behavior; in particular, 5-HT2C receptor agonists are shown to reduce nicotine intake and reinstatement. Of the selective 5-HT2C receptor agonists, lorcaserin has the best near-term potential for repurposing as a smoking cessation therapy, having been approved by the U.S. Food and Drug Administration for weight management. Preclinical findings implicate several potential behavioral mechanisms by which 5-HT2C receptor agonists might reduce drug intake, including drug-specific processes (e.g., incentive salience of drug cues, self-administration, reinstatement) and drug-nonspecific behaviors (e.g., reductions in impulsivity). To date, potential mechanisms of 5-HT2C receptor agonists have not been characterized in human studies of addiction. Given emerging interest in lorcaserin as a novel smoking cessation therapy, further studies are needed to evaluate its efficacy profile, including studies to evaluate candidate treatment mechanisms. Human laboratory studies play a pivotal role in drug development by providing a time- and cost-efficient means of validating preclinical findings, also providing an ideal platform for studying mechanisms of pharmacotherapy effects. This application proposes the first targeted human laboratory investigation of lorcaserin in smokers. The effects of lorcaserin vs. placebo on smoking-related outcomes will be evaluated in a double-blind, within-subjects, crossover study with human laboratory endpoints. We also propose the first human investigation of impulsivity subdomains as candidate mechanisms for 5-HT2C receptor agonists. By evaluating an approved 5-HT2C agonist with emergent efficacy for smoking cessation, this project has near-term potential to inform clinical applications of 5-HT2C agonists for addiction.